Many AVP antagonists have been reported in the literature. For example, des glycine d(CH.sub.2).sub.5 VAVP compounds are described in U.S. Pat. No. 4,469,679 to have potent VSP antaqonist activity as are others with an intact side chain, M. Manning et al. Nature, 308 652 (1984) and U.S. Pat. No. 4,491,577. Deletion of the proline at position 7 of such structures also gave potent V.sub.2 -antagonism, U.S. Pat. Nos. 4,481,194 and 4,481,193.
.alpha.-Methylamino acid units have previously been introduced into biologically active peptides to study the conformational effect of introducing a sterically crowded amino acid for its normal counterpart. The biological activities of the resulting peptides have been indifferent. In such bradykinins, moderate or complete reduction in agonist activity was observed; R. E. London et al., Int. J. Peptide Res. 19 334-342 (1982). In angiotensin, the agonist activity was lost with .alpha.-Me units at some positions of the peptide structure, but activity is retained with substitution at other positions, e.g. positions 4 and 8 (Turk et al., Mol. Pharmacol., 12, 217 (1976), G.R. Marshall, Circulation Research, II of Vol. 30 31, 143 (1972). Therefore, the art in general shows that the activity of biologically active peptides with structures which include an .alpha.-methylamino acid unit is unpredictable.
In the description herein and in the claims, the nomenclature common in the art of peptide and, more specifically, vasopressin chemistry is used. When no configuration is noted, the amino acid unit is in the L, or naturally occurring, form. The thio members of the .beta.-mercaptopropionic acid (1) and cysteine (6) units are added for clarity in certain structural formulas.
Exemplary of the peptide art designations used herein are the following: Pmp, .beta.-mercapto-.beta.,.beta.-cyclopentamethylenepropionic acid; .alpha.-Me-AA, .alpha.-methyl aliphatic amino acids; Aib, .alpha.-aminoisobutyric acid or .alpha.-methylalanine; .alpha.-MeVal, .alpha.-methylvaline; .alpha.-MePro, .alpha.-methylproline; .alpha.-MeLys, .alpha.-methyllysine; .alpha.-MeArg, .alpha.-methylarginine; Tyr, tyrosine; Tyr(Alk), C.sub.1-4 -alkyl ether of tyrosine; Gly, glycine; Gly(NH.sub.2), glycinamide; Arg, arginine; MeArg, N-methyl-arginine (N.alpha.-methyl); Cad, cadaverine; HArg, homoarginine; Phe, phenylalanine; 4'-AlkPhe, 4'-C.sub.1-4 -alkyl-phenylalanine; Val, valine; Chg, cyclohexylglycine; Gln, glutamic acid amide or glutamine; Cha, cyclohexylalanine; Lys, lysine; VSP, vasopressin; AVP, 8-arginine vasopressin; VAVP, 4-valine-8-arginine vasopressin; Asn, asparagine; Pro, proline; Cys, cysteine; Tos, tosylate; BHA, benzhydrylamine; DIEA, diisopropylethylamine; 4-MeBzl, 4-methylbenzyl; TFA, trifluoroacetic acid; DCC, dicyclohexylcarbodiimide; HOBT, 1-hydroxybenzotriazole; ACM, acetamidomethyl.